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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Significant progress is being made in understanding molecular events leading to lung cancer. Both susceptibility factors (molecular markers of risk) and the genetic alterations involved have been discovered. New techniques for early detection of lung cancer based on molecular changes (i.e. mutations in p53, K-ras and rb, amplification of myc and Her-2/neu, deletion of 3p, and microsatellite instability) in sputum or bronchoalveolar lavage fluid may be used as tools in diagnosis and prognosis, as well as in screening programs. These new findings should be transferred to the clinical environment. Multiple markers should be used, thereby increasing the chance of detecting the tumor or premalignant lesions. In the future, such research should be carried out in large prospective studies.
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PMID:[Lung cancer]. 969 5

A new human cancer cell line was established from a metastatic lesion of a small cell lung carcinoma (SCLC-R1) and maintained in continuous culture with a doubling time of 62 h. The SCLC-R1 line, whose ultrastructural features are presented, showed a diploid DNA content, a translocation involving chromosome 16 [t(16;?)(q24;?)] and noticeable deletions in the FHIT (fragile histidine triad) region in the short arm of chromosome 3 [del(3)(p14)] and in the telomeric region of the short arm of chromosome 12 [del(12)(p13)]. The involvement of 12p in metastatic small cell lung cancer is reported here for the first time. No amplification or rearrangements were evident in the c-myc, L-myc, N-myc, int-2, c-erbB-2, H-ras, K-ras, c-mos, and hst-1 genes by Southern blot analysis. Wild-type p53, RB, K-ras and H-ras genes were evident by polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) analysis. The neuron specific enolase (NSE) level was much higher in the cell line's cytosol than in the patient's serum and the cell line also had high expression of chromogranin A and cytokeratin 19. SCLC-R1 cells were sensitive to cisplatin, carboplatin and doxorubicin. The clinical history of the patient from whom the cell line was derived is reported. The characteristics of this new cell line indicate it to be a useful experimental model to investigate lung cancer biology and anticancer drug response.
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PMID:Chromosomal alterations, biological features and in vitro chemosensitivity of SCLC-R1, a new cell line from human metastatic small cell lung carcinoma. 971 81

Differences in tumor formation among inbred mouse strains with high (A/J) and low (C3H) susceptibility for lung cancer have been linked to a repetitive element within the second intron of the K-ras gene. The purpose of this investigation was to determine whether differences within the K-ras gene promoter region or the intron 2 polymorphism affect K-ras gene expression in lung tumors and target alveolar type II cells isolated from A/J and C3H mice. Ribonuclease protection assays were performed using RNA isolated from 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumors from each mouse strain and alveolar type II cells isolated from A/J and C3H mice. An 838 bp fragment of the murine K-ras gene promoter region was amplified by PCR, cloned and sequenced from both mouse strains. Promoter regions from both mouse strains were inserted into a luciferase reporter gene vector, with and without the second intron polymorphism, and transfected into sensitive, intermediate and resistant lung tumor cell lines. No significant differences in K-ras gene promoter activity was found between the two strains using these specific reporter gene constructs. Consistent with these results, levels of K-ras expression did not differ between alveolar type II cells, whole lung or tumors induced by NNK in A/J or C3H mice. Moreover, in lung tumor cell lines derived from mice with differing susceptibility for lung cancer, K-ras expression did not correlate with the growth rate of tumors induced in nude mice from these cell lines. These results indicate that factors involved in modulating the rapid clonal expansion of the mutated K-ras allele from A/J mice are not directly linked to expression of this gene. Other genetic changes or losses in conjunction with hypothesized modifier loci, such as the Par1 locus, must play a significant role in establishing the phenotypic strain differences for lung tumor formation.
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PMID:Effect of promoter and intron 2 polymorphisms on murine lung K-ras gene expression. 974 49

A search for serum factors that modulate the mutability of human cells has been attempted in the peripheral blood of lung cancer patients. Factors were separated by dye-ligand chromatography and first identified as those exhibiting the ability to enhance the frequency of drug-resistance mutations in human RSa cells. The frequency was assessed by estimation of the cloning efficiency of mutant cells resistant to ouabain-mediated cell killing (OuaR) after irradiation with far-ultraviolet light (UV, mainly 254-nm wavelength). Pre-culture of cells with medium containing the factors prior to UV irradiation led to about a 19- to 37-fold increase in the OuaR mutation frequency compared with that of cells irradiated but not treated with the factors. The enhancing activity was detected in the serum of all 7 lung cancer patients, although the serum itself, which had not been treated with chromatography, had little or no enhancing activity in all patients. No enhancing activity was detected in serum preparations from healthy donors. The enhancing activity of lung cancer serum factors on UV-induced mutagenicity was next confirmed by detecting an enhancement of K-ras codon 12 base substitution mutations in human RSb cells, as analyzed by polymerase chain reaction (PCR) and differential dot-blot hybridization. Our results, together with previous findings on suppression of mutagen-induced mutagenicity by human interferons, suggest the existence of extracellular factors that modulate the mutability of human cells.
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PMID:Detection of serum factors enhancing cell mutability from lung cancer patients by application of hypermutable human RS cells. 980 21

A high frequency of K-ras mutations may indicate preneoplastic changes in the bronchial epithelium as a result of genotoxic injury. With the use of sensitive detection techniques, we report a higher prevalence of K-ras mutations in bronchoalveolar lavage than has been reported previously for lung cancer. A PCR/ligase chain reaction technique was used to determine K-ras codon 12 mutations in a group of 52 bronchoalveolar lavage specimens from patients at risk of a second lung cancer. Of the specimens examined, 84% contained at least one mutation in K-ras codon 12, corroborated by an allele-specific hybridization method. These results suggest that point mutations in K-ras codon 12 are widespread in the bronchial epithelium. Based on these preliminary findings, further evaluation of this efficient sensitive assay to monitor K-ras status should be conducted in larger clinical cohorts where clinical outcomes will ultimately be available. Such a trial will define the utility of K-ras codon 12 mutation status as a marker of lung cancer.
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PMID:High frequency of K-ras codon 12 mutations in bronchoalveolar lavage fluid of patients at high risk for second primary lung cancer. 981 8

The K-ras mutation is one of the most common genetic alterations found in human lung cancer. To evaluate the prognostic value of ras gene alterations in lung cancer in a U.S. population, we have screened 173 human lung tumors, which included 127 adenocarcinomas, 37 squamous carcinomas, and 9 adenosquamous carcinomas, for mutations in the K-ras gene using the combination of the PCR and denaturing gradient gel electrophoresis. Forty-three tumors contained K-ras mutations. Of these, 41 were identified among the adenocarcinomas (32%), 1 among the squamous carcinomas (2.7%), and 1 among the adenosquamous carcinomas (11%). Forty of these mutations were found in codon 12 and consisted of 24 G to T transversions, 12 G to A transitions, 2 G to C transversions, and 1 double GG to TT mutation. Two other G to T transversions were found in codon 13, and 1 A to C transversion was found in codon 61. The data showed that gender did not seem to affect the incidence and the types of the K-ras mutations or amino acid changes. Examination of the mutations in adenocarcinomas in relation to overall survival showed no difference in adenocarcinomas with K-ras mutations compared with K-ras-negative adenocarcinomas. However, the substitution of the wild-type GGT (glycine) at codon 12 with a GTT (valine) or a CGT (arginine) showed a strong trend (P = 0.07) toward a poorer prognosis compared with wild-type or other amino acid substitutions. Substitution of the wild-type glycine for aspartate (GAT) showed a strong trend (P = 0.06) for a better outcome than the valine or arginine substitution. Although these trends will require larger patient populations for verification, these data suggest that the prognostic significance of K-ras mutations may depend on the amino acid substitution in the p21(ras) protein.
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PMID:Detection of K-ras mutations in lung carcinomas: relationship to prognosis. 981 85

In order to clarify the morphological and biological characteristics of well differentiated adenocarcinoma of the lung predominantly composed of goblet cells (WDAG), histopathological examinations, including some molecular biological procedures, were carried out using 42 surgical specimens of primary lung carcinoma which were predominantly (>50% of the total cell population) or totally composed of goblet cells. The subjects included 19 men and 21 women, ranging in age from 41 to 81 (mean 60 years old) with predominantly nodular, peripherally located lesions. Ultrastructural examination revealed characteristic apical microvillous filamentous core rootless (AFCR) in some, but not all, cases. Histologically, these AFCR corresponded well with structures stained by phosphotungstic acid hematoxylin (PTAH). The goblet cells of WDAG were divided into PTAH-positive (26 cases) and -negative (16 cases) groups. The PTAH-positive group had larger tumor size, greater number of intrapulmonary and extrapulmonary metastases and shorter disease-free interval. The immunoexpression of p53 protein (60%) and rate of K-ras point mutation (84%) were also higher in the PTAH-positive group. Therefore the goblet cell population of WDAG, though it may appear morphologically homogeneous under light microscopy, is actually composed of heterogeneous groups of cells with different histopathological characteristics and biological behavior.
Lung Cancer 1998 Nov
PMID:Immunohistochemical, ultrastructural and molecular study of well differentiated adenocarcinomas of the lung predominantly composed of goblet cells. 1002 18

Carcinogenesis is a multistep process in which many alterations in both genetic and epigenetic controls lead to a growth advantage for neoplastic cells. Hypermethylation has been established as the basis of genomic imprinting, but recent studies have also shown that alterations in genomic methylation patterns may contribute to tumorigenesis. The chemical 5-aza-2'-deoxycytidine (5-aza-dC) has been used both in vitro and in vivo to inhibit DNA methylation. In this study, we investigated the chemopreventive efficacy of 5-aza-dC in a well-established primary mouse lung tumor model. Five-week-old male (C3H/HeJ x A/J) F1 hybrid mice were treated for 24 consecutive weeks with 5-aza-dC, three times per week i.p. Lung tumors were induced with two consecutive weekly doses of 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone starting 1 week after initial treatment with 5-aza-dC. We demonstrated that 5-aza-dC exhibits a chemopreventive effect in this primary mouse lung tumor model which, like human lung adenocarcinomas, harbors an activating K-ras mutation. Treatment with 5-aza-dC resulted in a 23% reduction in tumor incidence, as well as a 42% reduction in tumor multiplicity. This work supports further investigation of methylation inhibitors likes 5-aza-dC for early intervention, prevention and treatment of lung cancer.
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PMID:5-Aza-2'-deoxycytidine is chemopreventive in a 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone-induced primary mouse lung tumor model. 1006 75

An increased prevalence of K-ras oncogene mutation in lung adenocarcinoma has been shown by PCR-primer-introduced restriction with enrichment for mutation alleles (PCR-PIREMA) experiments. In the present study we investigated whether this method is useful for the diagnosis of lung cancer in small pulmonary lesions, which are difficult to diagnose cytologically as lung cancer by bronchoscopic examination. We examined bronchoalveolar lavage fluid (BALF) cells from 33 patients with single nodular pulmonary lesions of less than 2 cm in diameter (measured on chest computed tomography scans) for K-ras (codon 12) mutation, by PCR-PIREMA. Transbronchial fiberscopic examinations had not revealed lung cancer cytologically in any of the patients. The final diagnoses for the 33 lesions were 20 adenocarcinomas, 5 cases of focal fibrosis, 5 cases of pneumonia, 1 case of tuberculosis, 1 hamartoma, and 1 case of lymph node swelling. BALF cell lysates were amplified and digested with a restriction enzyme to detect the K-ras oncogene. Only the normal K-ras was observed after the first amplification and digestion for each of the 33 patients. Three amplifications and digestions were performed for each sample. We detected mutation of K-ras in BALF cells from 15 (75%) of 20 lung cancer patients and in cells from only 4 (31%) of 13 patients with nonmalignant lesions. The detection rate of the K-ras mutation in lung cancer was significantly greater than that in nonmalignant lesions (P = 0.012). Our results indicate that the detection of the codon 12 K-ras mutation in BALF cells by PCR-PIREMA aids the diagnosis of lung cancer in patients with small pulmonary lesions with negative cytological findings.
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PMID:Detection of K-ras mutations of bronchoalveolar lavage fluid cells aids the diagnosis of lung cancer in small pulmonary lesions. 1010 Jul 14

Lung cancer incidence is increasing in women with little or no tobacco exposure, and the cause of this trend is not known. One possibility is increased sensitivity to environmental tobacco smoke in women nonsmokers diagnosed with lung cancer. To determine whether mutations associated with tobacco exposure are found in the lung tumors of women who are lifetime nonsmokers or occasional smokers, we compared the p53 and K-ras mutational spectra in lung carcinomas from 23 female nonsmokers, 2 female occasional smokers (< 10 pack-years), and 30 female long-term smokers (20-100 pack-years). We also looked for p53 and K-ras mutations in three carcinoid lung tumors, two from female nonsmokers and one from a female occasional smoker. For the p53 gene, exons 4-8 were examined for mutations; for the K-ras gene, exon 1 was examined. No mutations were found in the carcinoid tumors. In lung carcinomas, p53 mutations were identified in six (26.1%) of the cases from lifetime nonsmokers and consisted of five transitions (including three C to T, one G to A, and one T to C) and one T to A transversion. In comparison, p53 mutations were identified in 10 (31.3%) of the 32 lung carcinomas from short-term and long-term smokers and consisted of six transversions (four G to T, one A to T, and one G to C), one A to G transition, one C to T transition, and two deletions of one to four bp. Mutations in the p53 gene found in nonsmokers also occurred in either different codons or different positions within a codon compared with those seen in long-term smokers. K-ras mutations in codon 12 were identified in two lung carcinomas (8.7%) from lifetime nonsmokers. The K-ras mutations found were a G to T transversion and a G to A transition. Eight (25%) of the 32 lung carcinomas from smokers contained K-ras mutations in codons 12 and 13 (four G to T transversions and four G to A transitions). In addition, six silent mutations that are most likely polymorphisms were found in both smokers and nonsmokers. These results confirm that K-ras mutations are more frequent in smokers than in nonsmokers, but that the same type of mutation in the K-ras gene is found in both groups. In contrast, although the frequency of mutation in the p53 gene was similar in lifetime nonsmokers compared with long-term smokers, the types and spectra of mutation are significantly different. Two of the C to T transitions found in nonsmokers, but none of those found in smokers, occur at the C of a CpG site. These results suggest the mutagen(s) and/or mechanisms of p53 mutations in women nonsmokers are different from those responsible for p53 mutations in women smokers, which are probably largely induced by tobacco mutagens.
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PMID:Comparison of mutations in the p53 and K-ras genes in lung carcinomas from smoking and nonsmoking women. 1020 32


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